The present invention relates to substituted N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula 1 
wherein
R1, R2 and R3 which may be identical or different, may denote hydrogen, methyl or ethyl;
R4 may denote hydrogen, methyl or ethyl;
R5, R6 and R7 which may be identical or different, may denote hydrogen, methyl or ethyl;
R8 and R9 which may be identical or different, may denote hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy,
optionally in the form of the racemates, the enantiomers, the diastereomers and the mixtures thereof, or the pharmacologically acceptable acid addition salts thereof.
Preferred compounds of general formula 1 are those wherein
R1, R2 and R3 which may be identical or different, may denote hydrogen or methyl;
R4 may denote hydrogen or methyl;
R5, R6 and R7 which may be identical or different, may denote hydrogen or methyl, preferably methyl;
R8 may denote hydrogen, methyl, hydroxy or methoxy, preferably hydrogen or methyl,
R9 may denote hydrogen or methyl,
optionally in the form of the racemates, the enantiomers, the diastereomers and the mixtures thereof, as well as optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are the compounds of general formula 1 wherein
R1, R2 and R3 which may be identical or different, may denote hydrogen or methyl;
R4 may denote hydrogen or methyl;
R5, R6 and R7 may denote methyl;
R8 may denote hydrogen or methyl, preferably hydrogen;
R9 may denote hydrogen or methyl,
optionally in the form of the racemates, the enantiomers, the diastereomers and the mixtures thereof, as well as optionally the pharmacologically acceptable acid addition salts thereof.
Of exceptional importance according to the invention are those compounds of general formula 1 which are in the 1R configuration and, if R4 does not denote hydrogen, in the 2xe2x80x3S configuration. These stereoisomers which are preferred according to the invention may also be represented by general formula 1xe2x80x2 
wherein the groups R1, R2, R3, R4,R5, R6, R7, R8 and R9 may have the meanings given above.
Of particular interest are the following compounds of general formula 1:
(2R)-N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride;
(2R,2xe2x80x3S)-N-(2-allyloxy-propyl)-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hydrochloride.
If desired, the compounds of general formula (1) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable acid addition salts thereof with an inorganic or organic acid. Examples of acids for this purpose include for example succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Moreover, mixtures of these acids may also be used. The compounds claimed are blockers of the voltage-dependent sodium channel. These are compounds which displace batrachotoxin (BTX) with a high affinity (K1 less than 500 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances exhibit xe2x80x9cuse-dependencyxe2x80x9d while the sodium channels are blocked, i.e. in order to bind the substances at the sodium channel, the sodium channels first have to be activated. Maximum blockage of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances bind preferentially to sodium channels which are activated a number of times. As a result, the substances are in a position to become effective particularly in those parts of the body which are pathologically overstimulated. The compounds of general formula 1 according to the invention can thus be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
Consequently, in another aspect, the invention relates to the use of compounds of general formula 1 as pharmaceutical compositions, particularly as pharmaceutical compositions wherein the blocking of the voltage-dependent sodium channel may have a therapeutic benefit.
Preferably, the compounds of general formula 1 are used according to the invention to prepare a pharmaceutical composition for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative diseases.
Most preferably, the compounds of general formula 1 are used as described above according to the invention to prepare a pharmaceutical composition for the prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
The blocking action on the sodium channel may be demonstrated by the test system which tests the BTX binding to the sodium channel [S. W. Postma and W. A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as by patch-clamp experiments which show that the compounds according to the invention block the electrically stimulated sodium channel in a xe2x80x9cuse-dependentxe2x80x9d manner [W. A. Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. By a suitable choice of cell system (e.g. neuronal, cardiac, DRG cells) it is possible to test the effect of the substances on different subtypes of sodium channel.
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blocking of the veratridine-induced release of glutamate [S. Villanueva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin which opens the sodium channel permanently. This leads to an increased influx of sodium ions into the cell. This sodium influx leads to an increased release of glutamate in the neuronal tissue. The compounds according to the invention antagonise this release of glutamate.
Neuroprotective properties were demonstrated by a protective effect in a rat MCAO model [U. Pschorn and A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93-99 (1996)] and a malonate-induced lesion model [M. F. Beal, Annals of Neurology, 38, 357-366 (1995) and J. B. Schulz, R. T. Matthews, D. R. Henshaw and M. F. Beal, Neuroscience, 71, 1043-1048 (1996)].
Analgesic effects can be investigated in-models of diabetic neuropathy and in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett and Y. -K. Xie, Pain 33, 87-107 (1988)].
It has also been reported that sodium channel blockers can be used to treat cyclophrenia (manic depressive disorder) [J. R. Calabrese, C. Bowden, M. J. Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D. E. Bloom and D. J. Kupfer) 1099-1111. New York: Raven Press Ltd.].
The compounds 1 according to the invention may be prepared analogously to methods of synthesis known per se. One possible method of synthesis is shown in Diagram 1. The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols (2) shown as starting compounds in Diagram 1 may be obtained by methods of synthesis known in the art. In this respect reference is hereby made to European Patent Application EP-A-52 1422 and to International Patent Applications WO 97/06146 and WO 99/14199. 
The synthesis component 3 contains a leaving group X, which is preferably chlorine, bromine, hydroxy or a methoxy or ethoxy group. For a detailed explanation of the synthesis of the compounds of formula 1 according to the invention reference is made to the experimental procedures described below. One possible method of obtaining compounds of formula 1 wherein R9 denotes methyl is shown in Diagram 2.
Diagram 2: 
For a detailed explanation of the synthesis of the compounds of formula 1 according to the invention as shown in Diagram 2 reference is again made to the experimental procedures described below.